ES2563735T3 - Pharmaceutical dosage form comprising 6'-fluor- (N-methyl- or N, N-dimethyl-) -4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'- pyrano [3,4, b] indole] -4-amine - Google Patents

Abstract

Pharmaceutical dosage form for oral administration twice a day, once a day or less frequently, containing a pharmacologically active agent according to the general formula (I) ** Formula ** where R is -H or -CH3 , or a physiologically acceptable salt thereof, and a surfactant, the surfactant having an HLB value of at least 10.

Description

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Pharmaceutical dosage form comprising 6'-fluor- (N-methyl- or N, N-dimethyl-) -4-phenyl-4 ', 9'-dihydro-3'H- spiro [cyclohexane-1,1'- pyrano [3,4, b] indole] -4-amine.

FIELD OF THE INVENTION

The invention relates to a pharmaceutical dosage form for oral administration twice a day, once a day or less frequently, which contains a pharmacologically active agent according to the general formula (I)

image 1

where R is -H or -CH3,

or a physiologically acceptable salt thereof,

and a surfactant, the surfactant having an HLB value of at least 10.

The pharmacologically active agents according to the general formula (I) can also be referred to as 6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H -spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine. Unless expressly stated otherwise, this term also includes physiologically acceptable salts.

BACKGROUND OF THE INVENTION

The pharmacologically active agents according to the invention are known from the prior art and can be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, orally, rectally or locally, for example on the skin, in the mucous membranes or in the eyes. The compounds have analgesic properties and are particularly suitable for the treatment of acute, visceral, neuropathic or chronic pain (see, for example, WO 2004/043967 and WO 2008/040481).

WO 2006/082099 refers to a form of administration that is provided with a minimum breaking strength of 400 N while at the same time releasing the physiologically effective substance (A) at least partially delayed under physiological conditions.

Conventional analgesics are normally available as formulations that provide immediate release or as formulations that provide prolonged release.

On the one hand, formulations that provide immediate release after oral administration have the advantage that they lead to rapid release of the analgesic in the gastrointestinal tract. As a result, a relatively high dose of the analgesic is rapidly absorbed, which leads to high plasma levels in a short period of time and a rapid onset of pain relief, this is the analgesic effect begins shortly after administration. This is particularly desirable in case of acute pain.

However, at the same time, a rapid decrease in the analgesic effect is usually observed, since the metabolism and / or excretion of the analgesic cause a decrease in its plasma levels. For this reason, formulations that provide immediate release of analgesics should normally be administered frequently, for example eight times a day. This is not only harmful in terms of patient compliance, but it can also cause relatively high maximum plasma concentrations of the drug and large fluctuations between the maximum and minimum values of the drug concentration, which in turn can impair tolerability.

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On the other hand, formulations that provide prolonged release after oral administration have the advantage that they should be administered less frequently, usually once or twice a day. This improves patient compliance and can also reduce the maximum plasma concentrations of the drug and fluctuations between the maximum and minimum values of the drug concentration, which in turn can improve tolerability.

However, at the same time, the release of the analgesic in the gastrointestinal tract is prolonged. As a result, a relatively low dose of the analgesic is rapidly absorbed, which leads to low plasma levels and a delayed onset of pain relief, this is the analgesic effect begins well after the first administration.

In addition, since formulations that provide prolonged release normally contain higher doses of analgesics than formulations that provide immediate release, imply a greater risk of abuse. Older patients in particular often have difficulty ingesting solid pharmaceutical dosage forms. To cope with this problem, devices have been developed that allow solid pharmaceutical dosage forms to be shredded or pulverized ("tablet crushers"). These devices are used, for example, by health personnel in nursing homes. The pharmaceutical dosage forms are then not administered to assisted persons in the form of pills, etc., but in the form of powder, for example to avoid the difficulties involved in swallowing pills. However, the shredding of pharmaceutical dosage forms with these devices is problematic when these are prolonged release formulations. In general, the shredding leads to the destruction of the internal structure of the pharmaceutical dosage form, which is responsible for the prolonged release, thus eliminating the effect of prolonged release. Therefore, after the administration with frequency all the physiologically active substance originally contained in the pharmaceutical dosage form is released in a relatively short time, whereby the plasma concentration of the substance sharply reaches a comparatively very high value during a relatively long period. short (abrupt dose discharge). In this way, the original extended release formulations become immediate release formulations. However, depending on the physiological activity of the substance, this can cause considerable side effects and in extreme cases it can even lead to the patient's death (see, for example, JE Mitchell, Oral Pharmaceutical dosage forms That Should Not Be Crushed: 2000 Update, Hospital Pharmacy, 2000; H. Miller et al., To Crush or Not to Crush, Nursing 2000; R. Griffith et al., Tablet Crushing and thelaw: the implications for nursing; Prof. Nurse 2003). Intentional chewing of prolonged release formulations can also lead to an overdose of the substance contained therein. Sometimes patients deliberately chew the pharmaceutical dosage forms, although frequently ignoring the type and purpose of a prolonged release formulation, because they expect a faster effect.

Also known are formulations that provide a dual release mode, that is, a combination of immediate release and prolonged release (see, for example, CM. Lopez et al., Compressed Matrix Core Tablet as a Quick / Slow Dual-Component Delivery System Containing Ibuprofen, AAPS Pharm Sci Tech 2007; 8 (3), E1-E8). However, these formulations are usually based on immediate release units and extended release units that are arranged apart from each other and, consequently, these pharmaceutical dosage forms can only be prepared by specific and expensive methods.

An object of the invention is to provide pharmaceutical dosage forms containing 6'-fluor- (N-methyl- or- N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H-spiro [ cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine and which have advantages compared to the pharmaceutical dosage forms of the prior art. In particular, pharmaceutical dosage forms must provide good bioavailability and rapid pain relief after the first administration, but they must also have high tolerability, good patient compliance and safety.

This object was achieved through the content of the claims.

Surprisingly it has been found that 6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H- spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine has a relatively low water solubility. In addition, it has also been surprisingly proven that, despite such poor water solubility, pharmaceutical dosage forms can be prepared that provide an immediate release of 6'-fluor- (N-methyl- or N, N-dimethyl) -4 -phenyl-4 ', 9'-dihydro-3'H-spiro- [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine and good bioavailability. On the other hand it has also been surprisingly proven that 6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1, 1'-pyran [3,4, b] indole] -4-amine has a relatively large pharmacokinetic half-life (L / 2) and, therefore, provides a pharmacological activity for a relatively long period of time after administration.

Thus, surprisingly it has been found that after oral administration of the pharmaceutical dosage form containing the pharmacologically active agent according to the invention, it can be achieved

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a rapid onset of pain relief although, or even when, the pharmaceutical dosage form provides immediate release. Accordingly, the pharmaceutical dosage form according to the invention combines the advantageous properties of conventional formulations that provide immediate release (rapid pain relief due to an adequately high concentration of active ingredient just after administration of the pharmaceutical composition) with the advantageous properties of conventional formulations that provide a prolonged release (lasting analgesic effect due to an adequately high level of active ingredient over a prolonged period of time), and at the same time even overcomes the disadvantages of said conventional formulations. By taking the pharmacologically active agent in the formulation according to the invention, the patient can effectively combat his pain quickly and, at the same time, effectively treat it along a prolonged perforation without additional measures and simply by regular administration at intervals of 12 (or for example 24) hours.

It is particularly surprising that the pharmaceutical dosage form according to the invention not only allows the pharmacologically active agent to begin to flow rapidly in the plasma when the pharmaceutical dosage form is administered for the first time, which leads to a rapid onset of relief. of pain in the patient by immediate release, but at the same time ensures long-term therapeutic efficacy along a relatively large perforation (at least 12 hours). Therefore, the administration of the pharmaceutical dosage form according to the invention allows the pain suffered by a patient to be relieved quickly, without the analgesic effect disappearing rapidly.

The pharmaceutical dosage form according to the invention has good observance on the part of the patient and safety. Even if the pharmaceutical dosage form is manipulated according to the invention, for example with a tablet crusher, an abrupt discharge of the dose cannot occur: the crushing of the pharmaceutical dosage form does not accelerate the immediate release profile.

Figure 1 shows the average values of the numerical rating scale (NRS) measured over a 24-hour period after administration of different individual doses of the compound according to formula (I'b) (200, 400, 600 pg) compared with morphine and placebo in patients with acute postoperative pain after orthopedic surgery (bunionectomfa).

The invention relates to a pharmaceutical dosage form for oral administration twice a day, once a day or less frequently, which contains a pharmacologically active agent according to the general formula (I)

image2

where R is -H or -CH3,

or a physiologically acceptable salt thereof,

and a surfactant, the surfactant having an HLB value of at least 10.

The pharmacologically active agents according to the general formula (I) may also be referred to as "6'-fluor-N-methyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1 '-pyran [3,4, b] indole] -4-amine ", when R is -H, and as" 6'-fluor-N, N-dimethyl-4-phenyl-4', 9'-dihydro- 3'H-spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine ", when R is -CH3; for the purposes of the specification, the pharmacologically active agent according to formula (I) may also be designated as "6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H- spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine ".

In a preferred embodiment, the pharmacologically active agent according to the general formula (I) has a stereochemistry according to the general formula (I ')

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image3

where R is -H or -CH3, or a physiologically acceptable salt thereof.

In another embodiment of the pharmaceutical dosage form according to the invention, the compound of formula (I) is selected from

image4

in the form of a free base or physiologically acceptable salt thereof.

The free base according to the general formula (I'a) can be systematically designated as "1,1- (3- methylamino-3-phenylpentamethylene) -6-fluor-1,3,4,9-tetrahydropyran [3, 4-b] indole (trans) "or as" (1r, 4r) -6'-fluor-N-methyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1 '-pyran [3,4, b] indole] -4-amine ", respectively.

The free base according to the general formula (I'b) can be systematically designated as "1,1- (3- dimethylamino-3-phenylpentamethylene) -6-fluorine-1,3,4,9-tetrahydropyran [3, 4-b] indole (trans) "or as" (1r, 4r) -6'-fluor- N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1 , 1'-pyran [3,4, b] indole] -4-amine ", respectively.

The definition of the pharmacologically active agent according to the general formula (I) as used herein includes 6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro -3'H-spiro [cyclohexane-1,1'-pyrano [3,4, b] indole] -4-amine, derivatives and stereoisomers thereof in any possible form, including in particular solvates and polymorphs, salts, in particular acid addition salts, and corresponding solvates and polymorphs.

In a preferred embodiment, the pharmacologically active agent according to the general formula (I) is present as the sole diastereoisomer according to the general formula (I ').

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is present in the form of a mixture of diastereoisomers. This mixture may contain diastereoisomers in any proportion. For example, a diastereoisomeric mixture could contain diastereoisomers in a ratio 60 + 5: 40 + 5, 70 + 5: 30 + 5, 80 + 5: 20 + 5, 90 + 5: 10 + 5. Preferably, the pharmaceutical dosage form according to the invention contains the diastereoisomer according to the general formula (I ') in a diastereoisomeric excess (ed) of at least 50% ed, preferably at least 60% ed, so even more preferably at least 70% ed, especially preferably at least 80% ed, even more preferably at least 90% ed, most preferably at least 95% ed, and in particular at least one 98% ed, with respect to the other diastereoisomer (ie, trans versus cis and anti versus syn, respectively).

6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4-amine may be present in the pharmaceutical dosage form according to the invention in the form of a free base or in the form of an acid addition salt, any suitable acid capable of forming said addition salt may be used. of acid.

The conversion of 6'-fluor- (N-methyl- or N, N-dimethyl) -4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3 , 4, b] indole] -4-amine in a corresponding addition salt, for example by reaction with an acid

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suitable, can be carried out in a manner well known to those skilled in the art. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, smoking acid, lactic acid, citric acid, glutamic and / or aspartic acid. The salification is preferably carried out in a solvent, for example diethylether, diisopropylether, alkyl acetates, acetone and / or 2-butanone. In addition, trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.

The pharmaceutical dosage form contains the pharmacologically active agent according to the general formula (I) in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies depending on the compound, the treated disease, the severity of said disease, the treated patient and whether the pharmaceutical dosage form is intended for immediate or delayed release.

In a preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form according to the invention is at most 95% by weight, preferably at most 50% by weight, still more preferably at most 25% by weight, especially preferably at most 10% by weight, even more preferably at most 5% by weight, most preferably at most 1.0% by weight, and in particular at most 0.5% by weight.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form according to the invention is at least 0.001% by weight, preferably at least 0.005% by weight, so even more preferably at least 0.01% by weight, especially preferably at least 0.05% by weight, even more preferably at least 0.1% by weight, at least 0 , 5% by weight, and in particular at least 1.0% by weight.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form according to the invention is within the range of 0.320 + 0.315% by weight, preferably 0.320 + 0.310% by weight, still more preferably 0.320 + 0.305% by weight, especially preferably 0.320 + 0.300% by weight, even more preferably 0.320 + 0.295% by weight, most preferably 0.320 + 0.290% by weight and in particular of 0.320 + 0.285% by weight.

In another preferred embodiment, the content of the pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form according to the invention is within the range of 0.040 + 0.035% by weight, preferably 0.040 + 0.030% by weight, still more preferably 0.040 + 0.025% by weight, especially preferably 0.040 + 0.020% by weight, even more preferably 0.040 + 0.015% by weight, most preferably 0.040 + 0.010% by weight and in particular 0.040 + 0.005% by weight.

In another preferred embodiment, the content of the pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form according to the invention is within the range of 0.6 + 0.35% by weight, preferably 0.6 + 0.30% by weight, still more preferably 0.6 + 0.25% by weight, especially preferably 0.6 + 0.20% by weight, even more preferably 0.6 + 0.15% by weight, most preferably 0.6 + 0.10% by weight and in particular 0.6 + 0.05% by weight.

Unless explicitly stated otherwise, in the sense of the present invention the indication "% by weight" means weight of the respective ingredient by total weight of the pharmaceutical dosage form. If the pharmaceutical dosage form is coated with a film or encapsulated with an encapsulation medium that does not contain the pharmacologically active agent according to the general formula (I) and surrounds a nucleus which in turn contains the total amount of the pharmacologically active agent according to the general formula (I), the indication "% by weight" means the weight of the respective ingredient with respect to the total weight of the composition that forms said core.

Preferably, when the pharmaceutical dosage form is encapsulated or coated with a film, the pharmacologically active agent according to the general formula (I) is homogeneously distributed in the core of the pharmaceutical dosage form. Preferably, the encapsulation medium or the film coating does not contain a pharmacologically active agent according to the general formula (I). The dose of the pharmacologically active agent according to the general formula (I) preferably ranges from 0.1 pg to 5,000 pg, especially preferably between 0.1 pg and 1,000 pg, and completely preferably between 1.0 pg and 100 pg or between 30 pg and 600 pg.

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In a preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 25 + 20 pg, preferably 25 + 15 pg, especially preferably 25 + 10 pg , and preferably 25 + 5 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 40 + 35 pg, preferably 40 + 30 pg, even more preferably 40 + 25 pg, especially preferably 40 + 20 pg, even more preferably 40 + 15 pg, totally preferred 40 + 10 pg and in particular 40 + 5 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 50 + 35 pg, preferably 50 + 30 pg, even more preferably 50 + 25 pg, especially preferably 50 + 20 pg, even more preferably 50 + 15 pg, totally 50 + 10 pg, and in particular 50 + 5 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 60 + 35 pg, preferably 60 + 30 pg, even more preferably 60 + 25 pg, especially preferably 60 + 20 pg, even more preferably 60 + 15 pg, totally preferred 60 + 10 pg and in particular 60 + 5 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 100 + 90 pg, preferably 100 + 80 pg, even more preferably 100 + 60 pg, especially preferably 100 + 40 pg, even more preferably 100 + 20 pg, 100 + 10 pg completely, and in particular 100 + 5 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 200 ± 175 pg, preferably 200 ± 150 pg, even more preferably 200 ± 125 pg, especially preferably 200 ± 100 pg, even more preferably 200 ± 75 pg, totally preferably 200 ± 50 pg, and in particular 200 ± 25 pg.

In another preferred embodiment, the content of pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form is within the range of 400 ± 350 pg, preferably 400 ± 300 pg, even more preferably 400 ± 250 pg, especially preferably 400 ± 200 pg, even more preferably 400 ± 150 pg, totally preferably 400 ± 100 pg, and in particular 400 ± 50 pg.

In a preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 50 pg and 3,000 pg, especially preferably between 100 pg and 1,000 pg, even more preferably between 300 pg and 500 pg and totally preferred between 350 pg and 450 pg.

In another preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 200 pg and 400 pg and in particular between 250 pg and 350 pg.

For the purposes of this specification, the expression "being intended for use in the treatment of pain" is equivalent to "being adapted for use in the treatment of pain."

In a preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 200 pg and 400 pg and in particular between 250 pg and 350 pg.

In a preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 250 pg and 450 pg and in particular between 300 pg and 400 pg.

In another preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 300 pg and 500 pg and in particular between 350 pg and 450 pg.

In another preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 350 pg and 550 pg and in particular between 400 pg and 500 pg.

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In another preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of acute pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 400 pg and 600 pg and in particular between 450 pg and 550 pg.

In another preferred embodiment, the pharmaceutical dosage form is intended for use in the treatment of chronic pain, the dose of the pharmacologically active agent varying according to the general formula (I) preferably between 0.1 pg and 500 pg, so especially preferred between 1 pg and 250 pg, even more preferably between 5 pg and 100 p and totally preferred between 10 pg and 50 pg.

The pharmaceutical dosage form according to the invention is intended to be administered orally, that is, the pharmaceutical dosage form is adapted to be administered orally.

The pharmaceutical dosage form according to the invention is intended to be administered twice a day, once a day or less frequently, that is, the pharmaceutical dosage form is adapted to be administered twice a day, once a day. or less frequently.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is intended to be administered twice a day.

For the purposes of the specification, the expression "twice daily administration" (bid) preferably means that the pharmaceutical dosage form is adapted to be administered in accordance with a regimen comprising the administration of a first pharmaceutical dosage form according with the invention and subsequent administration of a second pharmaceutical dosage form according to the invention, both, the first and second pharmaceutical dosage form being administered, for a time interval of approximately 24 hours, but the second form being administered of pharmaceutical dosage not before 6 hours, preferably not before 8 hours, especially preferably not before 10 hours and in particular approximately 12 hours after administration of the first pharmaceutical dosage form.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is intended to be administered once a day.

For the purposes of the specification, the expression "administration once a day" (sid) preferably means that the pharmaceutical dosage form is adapted to be administered according to a regimen comprising the administration of a first pharmaceutical dosage form according with the invention and subsequent administration of a second pharmaceutical dosage form according to the invention, both the first and second pharmaceutical dosage form being administered, over a time interval of approximately 48 hours, but the second form being administered of pharmaceutical dosage not before 18 hours, preferably not before 20 hours, especially preferably not before 22 hours and in particular approximately 24 hours after the administration of the first pharmaceutical dosage form.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is intended to be administered once a day or less frequently.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is intended to be administered less frequently than once a day, preferably three times every four days (3/4), twice every three days (2/3 ), three times every five days (3/5), once every two days (1/2), three times a week (3/7), twice every five days (2/5), once every three days (1/3), twice a week (2/7), once every four days (1/4), once every five days (1/5), once every six days (1/6), or once a week (1/7). According to this embodiment, administration once every two days (1/2) is particularly preferred.

Specialists know perfectly well that administration regimens "twice a day, once a day or less frequently" can be done by administering a single pharmaceutical dosage form containing the total amount of the pharmacologically active agent according to the general formula (I ) to be administered at a particular time or, alternatively, by administering multiple dose units, that is, three or more dose units, the sum of said multiple dose units containing the total amount of the pharmacologically active agent according to the formula general (I) to be administered at that particular time, the individual dose units being provided to be administered simultaneously or for a short period of time, for example within 5, 10 or 15 minutes.

Preferably, the pharmaceutical dosage form according to the invention provides an immediate release of the pharmacologically active agent according to the general formula (I). Preferably, the pharmaceutical dosage form is specifically designed to provide immediate release of the pharmacologically active agent according to the general in vitro formula (I) of

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according to Ph. Eur. When the pharmaceutical dosage form is coated, for example with a coating soluble in gastric juices, the release kinetics is preferably controlled after the dissolution of said coating.

For the purposes of the specification, the concept of "immediate release" refers to any release profile that meets at least one of the following two requirements, preferably both. First, the pharmaceutical dosage form must disintegrate within 10 minutes or less after being exposed to a disintegration medium. Those skilled in the art know methods to determine the decay time. For example, it can be determined according to the USE XXIV decay analysis procedure, using, for example, an Erweka ZT-71 decay analyzer. Secondly, the pharmaceutical dosage form must release at least 70% by weight of the drug within 15 minutes after exposure to a dissolution medium. Preferably, the in vitro release properties of the pharmaceutical dosage form according to the invention are determined according to the method of vanes with plummet at 50, 75 or 100 rpm, preferably under in vitro conditions at 37 + 0.5 ° C in 900 ml of artificial gastric juices, pH 1.2, or under the same conditions in non-artificial gastric juices.

In a preferred embodiment, the pharmaceutical dosage form releases 900 ml of artificial gastric juices, pH 1.2 and 37 + 0.5 ° C under in vitro conditions, after 30 minutes according to the paddle method with plumbing 100 rpm, at least 50% by weight, preferably at least 60% by weight, especially preferably at least 70% by weight, even more preferably at least 80% by weight, completely preferably at at least 90% by weight and in particular at least 95% by weight of the pharmacologically active agent according to the general formula (I), with respect to the total amount of the pharmacologically active agent according to the general formula (l) contained Originally in the pharmaceutical dosage form.

The pharmaceutical dosage form according to the invention has an excellent period of validity and storage stability, that is, neither the chemical composition, nor the physical characteristics, nor the dissolution profile of the pharmaceutical dosage form are significantly altered with the storage.

In a preferred embodiment, the pharmaceutical dosage form according to the invention provides sufficient stability to the pharmacologically active agent according to the general formula (I) contained therein, such that, after storing the pharmaceutical dosage form at 40 + 2 ° C with a RH of 75% + 5%, for a minimum period of 6 weeks, preferably 3 months, the concentrations of degradation products and undesirable impurities respectively resulting preferably from a degradation or decomposition of the agent pharmacologically active according to the general formula (I) as such is at most 1.0% by weight, preferably at most 0.8% by weight, especially preferably at most 0.6%, still more preferably at most 0.4%, even more preferably at most 0.2% by weight, most preferably at most 0.1% by weight and in particular at most 0.05% by weight, with respect to the original content of the pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form, that is, its content before subjecting the pharmaceutical dosage form to storage.

It has been found that the pharmacologically active agent according to the general formula (I) can be decomposed by elimination of the group -NRCH3, resulting in 6'-fluor-4-phenyl-4 ', 9'-dihydro-3'H- Spiro [cyclohex-3-eno-1,1'-pyrano [3,4-b] indole], which appears to be pharmacologically inactive. Preferably, after storing the pharmaceutical dosage form at 40 + 2 ° C with a RH of 75% + 5%, or at 25 + 2 ° C with a RH of 60% + 5%, for a minimum time period of 6 weeks, preferably 3 months, the concentration of 6'-fluor-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohex-3-eno-1,1'-pyran [3,4-b ] indole] is a maximum of 1.0% by weight, preferably a maximum of 0.8% by weight, especially preferably a maximum of 0.6%, even more preferably a maximum of 0.4%, even more preferably as maximum 0.2% by weight, most preferably as maximum 0.1% by weight and in particular as maximum 0.05% by weight, with respect to the original content of the pharmacologically active agent according to the general formula (I) in the pharmaceutical dosage form, that is, its content before submitting the pharmaceutical dosage form to storage.

An accelerated trial generally accepted to determine the stability of a drug in accordance with the ICH guidelines and the FDA refers to the storage of a pharmaceutical formulation containing the drug (for example in its container and packaging). According to the ICH guidelines, the so-called accelerated storage test for pharmaceutical formulations should be carried out at 40 + 2 ° C with a RH of 75% + 5% for a minimum period of 6 months. In addition, the so-called long-term storage test for pharmaceutical formulations should be carried out at 25 + 2 ° C with a RH of not less than 60% + 5% for a minimum period of 12 months. If all the criteria for the accelerated storage test and long-term storage test conditions have been met

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During the 6-month period, the long-term storage test can be shortened to 6 months and the corresponding data can be doubled to obtain the estimated data for the 12-month period.

During storage, samples of the pharmaceutical formulation are taken at specific time intervals and analyzed for their drug content, presence of impurities, release profile and, if applicable, other parameters. According to the ICH guidelines, in all samples the purity of the drug should be> 98%, the drug content should be 95-105% (FDA guideline: 90110%). In addition, the pharmaceutical formulation should release> 80% of the drug within 30 minutes.

In the case of pills and capsules containing less than 50 mg of drug, a content uniformity test should also be carried out with 10 randomly chosen dosage forms. The pharmaceutical formulation meets the requirements if no individual content is outside the limits of 85% to 115% of the average content. If an individual content is outside these limits, then another 30 capsules should be analyzed. The preparation does not meet the requirements of the test if more than 3 individual contents are outside the limits of 85 to 115% of the average content, or if one or more individual contents are outside the limits of 75% to 125% of the average content.

In a preferred embodiment, after storing the pharmaceutical dosage form for 6 months under long-term storage conditions (25 ° C and a relative humidity of 60%) in a tightly sealed glass container, the degradation of the pharmacologically active agent of according to the general formula (I) it is not more than 2.0%, preferably 1.5%, particularly preferably 1.0% and 0.5% totally preferred.

In another preferred embodiment, after storing the pharmaceutical dosage form for 6 months under accelerated storage conditions (40 ° C and a relative humidity of 75%) in a hermetically sealed glass container, the degradation of the pharmacologically active agent according to the general formula (I) is not more than 4%, preferably 3%, especially preferably 2%, still more preferably 1% and completely preferred 0.5%.

Preferably, after storing the pharmaceutical dosage form for 6 months under long-term storage conditions (25 ° C and a relative humidity of 60%), the pharmaceutical dosage form releases 900 ml of artificial gastric juices under in vitro conditions , pH 1.2 and 37 + 0.5 ° C, after 30 minutes according to the method of vanes with plumb at 100 rpm at least 50% by weight, preferably at least 60% by weight, especially preferably at least 70% by weight and in a completely preferred manner at least 80% by weight of the pharmacologically active agent according to the general formula (I), with respect to the total amount of the pharmacologically active agent according to the general formula (I) originally contained in the pharmaceutical dosage form.

Preferably, after storing the pharmaceutical dosage form for 6 months under accelerated storage conditions (40 ° C and a relative humidity of 75%), the pharmaceutical dosage form releases 900 ml of artificial gastric juices under in vitro conditions, pH 1.2 and 37 + 0.5 ° C, after 30 minutes according to the method of vanes with sinker at 100 rpm, at least 50% by weight, preferably at least 60% by weight, especially preferably at least 70% by weight, and completely preferably at least 80% by weight of the pharmacologically active agent according to the general formula (I), with respect to the total amount of the pharmacologically active agent according to the formula general (I) originally contained in the pharmaceutical dosage form.

The absorption properties of a pharmacologically active agent by a pharmaceutical dosage form can be described by the pharmacokinetic parameters Cmax, tmax and AUC0-t. The determination of Cmax and tmax and the calculation of an AUC are well known to specialists and are described, for example, in Bauer, Fromming, Fuhrer, "Lehrbuch der Pharmazeutischen Technologie", 6th Edition (1999), and in Shargel, Wu -Pong, Yu, "Applied Biopharmaceuticals & Pharmacokinetics", 5th Edition (2005).

There is experimental evidence that the AUC0-t and the Cmax of the pharmacologically active agent according to the general formula (I) are proportional to the dose.

For the purposes of the specification, Cmax is the maximum plasma concentration of the pharmacologically active agent achieved after a single administration of the pharmaceutical dosage form.

For the purpose of specification, tmax is the time needed to reach Cmax.

For the purpose of specification, AUC0-t is the area under the curve from a single administration to time t of the last sample that contained an analytically quantifiable concentration of the pharmacologically active agent.

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For the purpose of the specification, AUCo-72h is the area under the baseline of the curve from after a single administration to 72 hours later.

Preferably, the Cmax / dose ratio is within the range of 0.01 m-3 to 3.00 m-3, preferably within the range of 0.02 to 2.50 m-3, especially preferably within the range of 0 , 04 to 2.00 m-3, and most preferably within the range of 0.06 to 1.69 m-3. In a preferred embodiment, the Cmax / dose ratio is within the range of 0.40 + 0.35 m-3, preferably 0.40 + 0.30 m-3, especially preferably 0.40 + 0.25 m -3, still more preferably 0.40 + 0.20 m-3, even more preferably 0.40 + 0.15 m-3, completely preferably 0.40 + 0.10 m-3 and in particular 0.40 + 0.05 m-3. In another preferred embodiment, the Cmax / dose ratio is within the range of 0.80 + 0.70 m-3, preferably 0.80 + 0.60 m-3, especially preferably 0.80 + 0.50 m -3, still more preferably 0.80 + 0.40 m-3, even more preferably 0.80 + 0.30 m-3, completely preferably 0.80 + 0.20 m-3 and in particular 0.80 + 0.10 m-3. In another preferred embodiment, the Cmax / dose ratio is within the range of 1.20 + 1.05 m-3, preferably 1.20 + 0.90 m-3, especially preferably 1.20 + 0.75 m -3, still more preferably 1.20 + 0.60 m-3, even more preferably 1.20 + 0.45 m-3, completely preferably 1.20 + 0.30 m-3 and in particular 1.20 + 0.15 m-3.

Preferably, tmax is within the range between 15 minutes and 24 hours, preferably within the range between 20 minutes and 20 hours, especially preferably within the range between 0.5 and 16 hours, most preferably within the range between 1 and 12 hours, and in particular within the interval between 2 and 10 hours. In a preferred embodiment, tmax is within the range of 4 + 3.5 hours, preferably 4 + 3 hours, especially preferably 4 + 2.5 hours, even more preferably 4 + 2 hours, even more preferably 4 + 1.5 hours, preferably 4 + 1 hours, and in particular 4 + 0.5 hours. In another preferred embodiment, tmax is within the range of 8 + 7 hours, preferably 8 + 6 hours, especially preferably 8 + 5 hours, even more preferably 8 + 4 hours, even more preferably 8 + 3 hours , preferably 8 + 2 hours, and in particular 8 + 1 hours. In another preferred embodiment, tmax is within the range of 12 + 11 hours, preferably 12 + 9 hours, especially preferably 12 + 7 hours, even more preferably 12 + 5 hours, even more preferably 12 + 3 hours , preferably 12 + 2 hours, and in particular 12 + 1 hours.

Preferably, the ratio AUC0-t / dose is within the range of 0.3 to 20 h / m3, preferably within the range of 0.4 to 18 h / m3, especially preferably within the range of 0.5 to 16 , 5 h / m3, and preferably within the range of 0.55 to 12.5 h / m3. In a preferred embodiment, the ratio AUC0-t / dose is within the range of 3 + 2.5 h / m3, preferably 3 + 2 h / m3, especially preferably 3 + 1.5 h / m3, still more preferred 3 + 1 h / m3, even more preferably 3 + 0.75 h / m3, totally preferred 3 + 0.5 h / m3, and in particular 3 + 0.25 h / m3. In another preferred embodiment, the ratio AUC0-t / dose is within the range of 6 + 5 h / m3, preferably 6 + 4 h / m3, especially preferably 6 + 3 h / m3, even more preferably 6 + 2 h / m3, even more preferably 6 + 1.5 h / m3, totally preferred 6 + 1 h / m3, and in particular 6 + 0.5 h / m3. In another preferred embodiment, the ratio AUC0-t / dose is within the range of 9 + 8 h / m3, preferably 9 + 7 h / m3, especially preferably 9 + 5 h / m3, even more preferably 9 + 4 h / m3, even more preferably 9 + 3 h / m3, totally preferred 9 + 2 h / m3, and in particular 9 + 1 h / m3.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is monolithic.

In another preferred embodiment, the pharmaceutical dosage form according to the invention comprises a core surrounded by a coating or an encapsulation material. In a preferred embodiment, the core is liquid and the pharmacologically active agent according to the general formula (I) is dispersed, preferably dissolved, in the liquid.

Preferably, the pharmaceutical dosage form according to the invention provides the pharmacologically active agent according to the general formula (I) in the form of auto (micro) emulsifying drug delivery systems, solid solutions, nanoparticles, cyclodextrin complexes, liposomes. , micelles, micronized and / or amorphous states.

In general terms, the options for formulating low water soluble drugs include solid crystalline, amorphous and lipid formulations.

The dissolution rate of the pharmacologically active agent of the crystalline formulations can be increased by reducing the particle size, thereby increasing the surface area for dissolution, for example by conventional micronization of the pharmacologically active agent to particle sizes of about 2-5 pm. In some cases this is not enough and technology is applied.

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nanocrystals The nanocrystals have a particle size of 100-250 nm, which can be obtained by grinding with balls or by dense gas or supercritical fluid technology.

Solid solutions provide and maintain the pharmacologically active agent in an amorphous state immobilized in a polymer. Amorphous solutions may contain surfactants and polymers, thus providing surface activity during dispersion upon contact with water. Solid solutions can be formed using various technologies, such as spray drying and fusion extrusion.

Lipid formulations of different characteristics can be used to disperse and form micellar solutions, including simple solutions and self-emulsifying drug delivery systems (self-emulsifyingdrugdeliverysystems - SEDDS). Depending on the excipients, some require digestion (for example, simple oleaginous fluids), others can be easily absorbed without digestion. Lipid formulations are classified according to the system of classification of lipid formulations (lipidformulationclassificationsystem - LFCS) as follows:

 Excipients in formulation

 Formulation content (% by weight) Type I Type II Type IIIA T'p ° T'po IIIB IV

 Oil: triglycerides or mixture of monoglycerides and diglycerides Water insoluble surfactants (HLB <12) Water soluble surfactants (HLB> 12) Hydrophilic co-solvent

 100 40-80 40-80 <20 - - 20-60 - - 0-20 - - 20-42 20-50 30-80 - - 0-40 20-50 0-50

Another option is the formation of cyclodextrin complexes where the pharmacologically active agent is located in the cyclodextrin cavity and is thus molecularly present in a more soluble form in the presence of aqueous media. The success of the installation depends largely on the quality of the cyclodextrins and the physicochemical properties and the size of the pharmacologically active agent.

In a preferred embodiment, the pharmaceutical dosage form according to the invention can be considered as a self-emulsifying drug delivery system (SEDDS).

To this end, the pharmacologically active agent according to the general formula (I) is preferably incorporated into a self-emulsifying formulation. A so-called self-emulsifying drug delivery system (SEDDS) is a drug delivery system that uses an emulsion obtained by chemical means rather than by mechanical means. That is, through an intrinsic property of the drug formulation, rather than by special mixing and handling. Said formulation is diluted in aqueous media and results in an emulsion. If the average droplet size is less than or equal to 50 nm, the self-emulsifying drug delivery system (SEDDS) is designated as the self-emulsifying drug delivery system (self-micro emulsifyingdrugdeliverysystem - SMEDDS). According to the classification system of lipid formulations, these formulations are typically assigned to the group of type III formulations.

A preferred subset of SEDDS are self-emulsifying oily formulations (SEOF). SEOFs typically comprise a natural or synthetic oil, surfactant and hydrophilic solvent, and sometimes co-solvents. The main characteristic of SEOF is its ability to form fine emulsions of oil in water or microemulsions after gentle agitation after dilution by aqueous phases. These formulations can be dispersed in the gastrointestinal lumen to form microemulsions or fine emulsions after dilution with gastrointestinal fluids.

In another preferred embodiment, the pharmaceutical dosage form contains the pharmacologically active agent according to the general formula (I) in the form of a solid solution, that is, molecularly dispersed in a solid matrix. The solid solution preferably comprises the pharmacologically active agent according to the general formula (I) in a dispersed molecular form and an amorphous polymer matrix with a comparatively large specific surface. The pharmacologically active agent according to the general formula (I) is preferably present in a dispersed molecular form, that is, the compound is actually dissolved and uniformly dispersed in the solidified solution. The particle size of the compound is neither microcrystalline nor fine crystalline. The typical particle size preferably ranges from 0.1 to 1 pm.

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is provided by a nanotechnological formulation with an average nanoparticle size preferably less than 1 pm. In a preferred embodiment, the pharmacologically active agent of

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according to the general formula (I) it is provided in nanonized form. In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is mixed with nanoparticles, preferably selected from organic nanoparticles and inorganic nanoparticles, and is therefore adsorbed on the surface of said particles.

Organic nanoparticles preferably contain small proteins that are present in the form of a cluster or agglomerate of small proteins, oligopeptides or lipids.

Inorganic nanoparticles preferably contain crystalline silicates. These silicates are of mineral origin or artificial silicates, such as metalosilicates (for example zeolites). In a preferred embodiment, the nanoparticles are modified so that they carry an electrostatic charge. The nanoparticles preferably consist of ultrafine ground silicates and the pharmacologically active agent according to the general formula (I) is preferably attached to the microporous surface of the nanoparticles.

Those skilled in the art know the formation of nanoparticles. One method is to produce colloidal nanoparticles as supports for the release of oral drugs by spraying the pharmacologically active agent according to the general formula (I) under pressure, at a defined temperature, together with a suitable support material such as protamine, through of nozzles equipped with perforated filters, in very refrigerated towers. The result of rapid cooling is an amorphous phase of nanoparticles. Another method is to mix the pharmacologically active agent according to the general formula (I) with suitable macromolecules in solution. By adding hydrophobic compounds, the solvent molecules are removed from the solution and a desolvation occurs. Therefore, small particles are formed in which the pharmacologically active agent is integrated according to the general formula (I). A crosslinker can also be added to the solution to harden the formed nanoparticles.

To produce, for example, a solid lipid nanoparticle, the high pressure homogenization method and subsequent spray cooling can be used. Preferably, the pharmacologically active agent according to the general formula (I) is dissolved in a suitable solvent or in the form of submicron particles. If applicable, a lipid carrier and a surfactant can also be added to the solution. Finally, it is also possible to add fine fillers as the outer phase and as fluidizers and other surfactants to fill the formulation obtained for example in capsules, such as hard gelatin capsules.

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is provided in the form of (inclusion) cyclodextrin complexes.

Cyclodextrins are composed of sugar molecules that form a ring and typically include 5 or more units of α-D-pyranoside attached at position 1-4. The normal amount of connected sugar monomers ranges between 6 and 8 units. A six-membered sugar ring molecule is called a-cyclodextrin. A seven-member sugar ring molecule is called p-cyclodextrin and an eight-member sugar ring molecule is called y-cyclodextrin. The form of these compounds ceases a toroid with the major and minor openings exposed to the solvent. Due to this formation, the inner part of the toroid is not hydrophobic, but is considerably less hydrophilic than the aqueous environment and, consequently, can accommodate hydrophobic molecules. The outside of the toroid is hydrophilic enough to make cyclodextrins water soluble.

The inclusion of the pharmacologically active agent according to the general formula (I) in cyclodextrins greatly modifies the physical and chemical properties. In most cases, the mechanism of controlled degradation of these complexes and the release of the resulting drug are based on a change in the pH of aqueous solutions, which leads to the dissociation of hydrogen or ionic bonds between the cyclodextrins and the molecules included. Other alternative means for breaking the complexes take advantage of the heating or the action of enzymes capable of dissociating the a1-4 bonds between the a-D-glycopyranosides.

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is provided in the form of liposomes. The liposomes are preferably composed of phospholipids and are preferably spherical in shape. The wrapping of this form preferably consists of a laminar or bilayer structure. Another type of phospholipid structure consists of a monolayer.

Phospholipids comprise amphiphilic molecules, that is, the molecules have a hydrophobic part (lipophilic) and a hydrophilic part (lipophilic). In the presence of water, the hydrophilic part is drawn to the water and forms a surface in front of the water, while the hydrophobic part is repelled by the water and forms a surface away from the water. Therefore, amphiphilic molecules are themselves arranged in one of the types mentioned.

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The bilayer structures are preferably arranged in a spherical shape, the inner part of which is filled with an aqueous solution. This type is called "liposome." The hydrophobic parts of the molecules are facing each other in the center of the layer and the hydrophilic parts of the molecules are located opposite the water molecules outside the liposome. The aqueous solution inside the liposome is the same as outside the liposome. Thus, the ingredients dissolved in this aqueous solution, for example the pharmacologically active agents according to the general formula (I), are within the liposome. The normal diameter of the liposomes ranges between 25 nm and 1 pm. The smallest (25 nm - 200 nm) are formed by a single bilayer, while the larger ones (200 nm - 1 pm) include more bilayer envelopes on top of each other.

Monolayer structures are also arranged in spherical shapes. Due to the amphiphilic character of the molecules and the spherical shape of the monolayer structures, the inner part of the spherical structures is filled with / formed by the hydrophobic parts of the molecules. These types are called micelles. Within the structure there is no solvent. In a preferred embodiment, the inner parts of the micelles contain the pharmacologically active agents according to the general formula (I).

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is provided in a micronized state. Through a micronization technique, particles of the pharmacologically active agent can be prepared according to the general formula (I) with a nanometer scale diameter. These particles have a great surface-volume relationship.

Grinding and crushing is a useful method to obtain particles on a nanometric scale. Sophisticated micronization techniques include RESS (rapid expansion of supercriticalsolutions - rapid expansion of supercritical solutions), SAS (supercritical anti solvent - supercritical antisolvent) and PGSS (particlesfrom gas saturatedsolutions - particles of saturated gas solutions).

The RESS method uses a supercritical fluid where the pharmacologically active agent is dissolved according to the general formula (I) under high pressure and temperature, thus producing a homogenous supercritical phase. After expanding the solution through a nozzle, small particles are formed. Due to the expansion at the end of the nozzle, the pharmacologically active agent according to the general formula (I) dissolved precipitates as crystals and encloses small amounts of the solvent. The solvent changes from the supercritical fluid state to the normal state, preferably the gas phase, and breaks the crystals from the inside out. In this way and due to the fact that the crystals collide with each other, particles with a nanometer scale diameter are formed.

In the SAS method, the pharmacologically active agent according to the general formula (I) is dissolved in a preferably organic solvent. To the solution, a supercritical fluid is added under pressure and its dissolution in the solvent is also forced. Consequently, the volume of the entire system increases and the solubility of the pharmacologically active agent according to the general formula (I) decreases. Due to this decrease in solubility, the compound according to the general formula (I) precipitates and forms particles of small diameter.The PGSS method is similar to the SAS method. In this case, the pharmacologically active agent according to the general formula (I) melts and a supercritical fluid dissolves in the melt. Due to the expansion through a nozzle, the pharmacologically active agent according to the general formula (I) precipitates and forms particles on a nanometric scale.

In a preferred embodiment, the pharmaceutical dosage form according to the invention contains

ffis ffis ffis

- a non-ionic surfactant (for example Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol® HS 15, sorbitan monooleate, poloxamer 407, Labrafil® M-1944CS, Labrafil® M-2125CS, Labrasol®, Gelucire® 44/14, Softigen® 767, and fatty acid monoesters and diesters of PEG 300, 400 or 1750); I

- an anionic surfactant, such as sodium lauryl sulfate (sodium dodecyl sulfate, for example Texapon® K12), sodium cetyl sulfate (for example Lanette E®), sodium cetyl stearyl sulfate, sodium stearyl sulfate, dioctyl sulphosuccinate sodium ( sodium docusate); I

- a water-insoluble lipid (for example castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, cartam oil, sesame oil, soybean oil, hydrogenated vegetable oils , hydrogenated soybean oil, and medium chain triglycerides of coconut oil and palm oil); I

- an organic liquid / semi-solid (for example beeswax, d-alpha-tocopherol, oleic acid, monoglycerides and medium chain diglycerides); I

- a cyclodextrin (for example alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrins, and sulfobutylether-beta-cyclodextrin); I

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- a phospholipid (for example hydrogenated soy phosphatidylcholine, diestearoylphosphatidyl glycerol, L-alpha-dimiristoylphosphatidylcholine, and L-alpha-dimiristoylphosphatidyl glycerol.

Preferably, the pharmacologically active agent according to the general formula (I) is molecularly dispersed in a matrix.

In a preferred embodiment, the pharmacologically active agent according to the general formula (I) is molecularly dispersed in a non-crystalline matrix.

In another preferred embodiment, the pharmacologically active agent according to the general formula (I) is molecularly dispersed in a non-amorphous matrix.

Preferably, the pharmacologically active agent according to the general formula (I) is homogeneously distributed in the pharmaceutical dosage form according to the invention. The contents of pharmacologically active agent according to the general formula (I) of two segments of the pharmaceutical dosage form with a volume of 1.0 mm 3 each preferably differ from each other no more than + 10%, especially preferably no more than + 7.5%, even more preferably no more than + 5.0%, totally preferred no more than 2.5% and in particular no more than + 1.0%. When the pharmaceutical dosage form is encapsulated or coated with a film, said two segments of the pharmaceutical dosage form with a volume of 1.0 mm 3 each preferably consist of core segments, that is, they do not contain encapsulation medium or coating. of film, respectively.

Preferably, the pharmaceutical dosage form according to the invention is characterized by a relatively homogeneous distribution of density. Preferably, the densities of two segments of the pharmaceutical dosage form with a volume of 1.0 mm3 each differ from each other no more than + 10%, especially preferably not more than + 7.5%, still more preferably no more than + 5.0%, totally preferred no more than 2.5% and in particular no more than + 1.0%. When the pharmaceutical dosage form is encapsulated, said two segments of the pharmaceutical dosage form with a volume of 1.0 mm 3 each preferably consist of core segments, that is, they do not contain encapsulation medium or film coating, respectively.

The pharmaceutical dosage form also contains a surfactant.

For the purposes of the specification, the term "surfactant" refers to any compound that contains at least one hydrophobic group and at least one hydrophilic group. Preferably, the surfactant contains at least one hydrophobic terminal group (tail) and at least one hydrophilic terminal group (head).

The hydrophobic group is preferably selected from the group consisting of the hydrocarbon, alkylene, fluorocarbon and siloxane groups.

In a preferred embodiment, the surfactant contains at least one aliphatic group with at least 3 carbon atoms, especially preferably at least 4 carbon atoms, even more preferably at least 6 carbon atoms, even more preferably from 6 to 30 carbon atoms and preferably from 8 to 24 carbon atoms. The aliphatic group may be a saturated or unsaturated, branched or unbranched (linear), terminal or interior aliphatic group.

Preferably, the surfactant contains at least one group derivable from a saturated or unsaturated fatty acid or from a saturated or unsaturated fatty alcohol, said group preferably consisting of an ether group, carboxylic acid ester or sulfuric acid ester. Preferably, the saturated or unsaturated fatty acid or fatty alcohol includes at least 6 carbon atoms, especially preferably 6 to 30 carbon atoms and most preferably 8 to 24 carbon atoms.

In a preferred embodiment, the surfactant contains at least one group derived from a saturated or unsaturated fatty acid, preferably a C8 to C30 fatty acid, especially preferably a C8 to C24 fatty acid, and most preferably a C12 fatty acid. to C22. Examples of suitable fatty acids are lauric, mystic, palmic, stearic, arachidic, behenic, lignoceric, 12-hydroxystearic, oleic and ricinoleic acids.

In another preferred embodiment, the surfactant contains at least one group derived from a saturated or unsaturated fatty alcohol, preferably a C8 to C30 fatty alcohol, especially preferably a C8 to C24 fatty alcohol, and most preferably a C12 fatty alcohol. to C22. Examples of suitable fatty alcohols are cetyl alcohol, stearyl alcohol, 2-octyldodecan-1-ol and 2-hexyldecan-1-ol.

Preferably, the surfactant has a molecular weight of at most 20,000 g / mol, preferably at most 15,000 g / mol, especially preferably at most 10,000 g / mol,

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even more preferably at most 5,000 g / mol, even more preferably at most 4,000 g / mol, most preferably at most 3,000 g / mol, and in particular within the range of 100 g / mol a 2,500 g / mol.

Preferably, the surfactant is contained in a matrix where the pharmacologically active agent according to the general formula (I) is dispersed, preferably molecularly.

In a preferred embodiment, the pharmacologically active agent according to the general formula (I) and the surfactant are homogeneously distributed in a matrix, so that the matrix does not contain any segment in which the pharmacologically active agent agrees with the general formula (I) it is present in the absence of the surfactant or in which the surfactant is present in the absence of the pharmacologically active agent according to the general formula (I).

The pharmaceutical dosage form contains a surfactant. In a preferred embodiment, the pharmaceutical dosage form contains a mixture of two or more surfactants.

In a preferred embodiment, the surfactant acts as an oil / water emulsifier (O / W). In another preferred embodiment, the surfactant acts as a water / oil emulsifier (W / O).

The pharmaceutical dosage form contains a surfactant with a hydrophilic-lipophilic balance (HLB) of at least 10 or preferably at least 11. Especially preferably, the hydrophilic-lipophilic balance (HLB) is at least 12 or at least 13. Totally preferably, the hydrophilic-lipophilic balance (HLB) ranges from 14 to 16.

In another preferred embodiment, the hydrophilic-lipophilic (HLB) balance of the surfactant is at least 27, preferably at least 29, especially preferably at least 31, even more preferably at least 33, even more preferably at minus 35, completely preferably at least 37 and in particular at least 39. A particularly preferred surfactant of this type is sodium lauryl sulfate with an HLB value of about 40.

In a preferred embodiment, the HLB value of the surfactant is within the range of 12 + 2, especially preferably 12 + 1.5, completely preferably 12 + 1, and in particular 12 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 14 + 3.5, preferably 14 + 3, especially preferably 14 + 2.5, even more preferably 14 + 2, even more preferably 14 + 1.5, most preferably 14 + 1, and in particular 14 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 15 + 3.5, preferably 15 + 3, especially preferably 15 + 2.5, even more preferably 15 + 2, even more preferably 15 + 1.5, most preferably 15 + 1, and in particular 15 + 0.5. In another preferred embodiment the HLB value of the surfactant is in the range of 16 + 3.5, preferably 16 + 3, especially preferably 16 + 2.5, even more preferably 16 + 2, even more preferably 16 + 1.5, most preferably 16 + 1, and in particular 16 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 18 + 3.5, preferably 18 + 3, especially preferably 18 + 2.5, even more preferably 18 + 2, even more preferably 18 + 1.5, most preferably 18 + 1, and in particular 18 + 0.5.

In another preferred embodiment the HLB value of the surfactant is in the range of 30 + 3.5, preferably 30 + 3, especially preferably 30 + 2.5, even more preferably 30 + 2, even more preferably 30 + 1.5, preferably 30 + 1, and in particular 30 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 32 + 3.5, preferably 32 + 3, especially preferably 32 + 2.5, even more preferably 32 + 2, even more preferably 32 + 1.5, completely preferably 32 + 1, and in particular 32 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 34 + 3.5, preferably 34 + 3, especially preferably 34 + 2.5, even more preferably 34 + 2, even more preferably 34 + 1.5, most preferably 34 + 1, and in particular 34 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 36 + 3.5, preferably 36 + 3, especially preferably 36 + 2.5, even more preferably 36 + 2, even more preferably 36 + 1.5, most preferably 36 + 1, and in particular 36 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 38 + 3.5, preferably 38 + 3, especially preferably 38 + 2.5, even more preferably 38 + 2, even more preferably 38 + 1.5, most preferably 38 + 1, and in particular 38 + 0.5. In another preferred embodiment the HLB value of the surfactant is within the range of 40 + 3.5, preferably 40 + 3, especially preferably 40 + 2.5, even more preferably 40 + 2, even more preferably 40 + 1.5, most preferably 40 + 1, and in particular 40 + 0.5.

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The surfactant can be ionic, amphoteric or non-ionic.

Suitable amphoteric surfactants include phospholipids, in particular lecithins such as soy lecithins.

In a preferred embodiment, the pharmaceutical dosage form contains an ionic surfactant, in particular an anionic surfactant.

Suitable anionic surfactants include, but are not limited to, sulfuric acid esters such as sodium lauryl sulfate (sodium dodecyl sulfate, for example Texapon® K12), sodium cetyl sulfate (for example Lanette E®), sodium cetyl stearyl sulfate , sodium stearyl sulfate, sodium dioctylsulfosuccinate (sodium docusate); and the corresponding potassium or calcium salts thereof.

Preferably, the anionic surfactant has the general formula (Il-a)

CnH2n + iO-SO3'M + (ll-a),

where n is an integer from 8 to 30, preferably from 10 to 24, especially preferably from 12 to 18; and M is selected from Li, Na, K, NH4, 1/2 Mg and 1/2 Ca2.

Other suitable anionic surfactants include colic acid salts, including sodium glycolate (for example Konakion® MM, Cernevit®), sodium taurocholate and the corresponding potassium or ammonium salts.

In another preferred embodiment, the pharmaceutical dosage form contains a non-ionic surfactant. Suitable non-ionic surfactants include, but are not limited to,

fatty alcohols that can be linear or branched, such as cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, 2-octyldodecan-1-ol and 2-hexyldecan-1-ol;

sterols, such as cholesterol;

partial esters of sorbitan fatty acid such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sadarate, sorbitan monooleate, sorbitan sesquioleate and sorbitan trioleate;

partial esters of polyoxyethylene sorbitan fatty acid (polyoxyethylene sorbitan fatty acid esters), preferably a polyoxyethylene sorbitan fatty acid monoester, a polyoxyethylene sorbitan fatty acid diester, or a polyoxyethylene sorbitan fatty acid triester; for example mono- and trilauric, palmityl, stearyl and olefin esters, such as those of the type known by the name "polysorbate" and commercially available under the trade name "Tween" including Tween® 20 [polyoxyethylene monolaurate (20) sorbitan] Tween® 21 [polyoxyethylene (4) sorbitan] monolaurate, Tween® 40 [polyoxyethylene (20) sorbitan monopalmitate], Tween® 60 [polyoxyethylene (20) sorbitan monostearate], Tween® 65 [polyoxyethylene (20) sorbitan triestearate ], Tween® 80 [polyoxyethylene (20) sorbitan monooleate], Tween 81 [polyoxyethylene (5) sorbitan monooleate], and Tween® 85 [polyoxyethylene (20) sorbitan trioleate]; preferably a polyoxyethylene sorbitan fatty acid monoester according to the general formula (ll-b)

image5

ch3

(ll-b)

where (w + x + y + z) is within the range of 15 to 100, preferably 16 to 80, especially preferably 17 to 60, even more preferably 18 to 40 and totally preferred 19 to 21; and the alkylene is an optionally unsaturated alkylene group comprising

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6 to 30 carbon atoms, especially preferably 8 to 24 carbon atoms and most preferably 10 to 16 carbon atoms;

polyoxyethylene glycerol fatty acid esters, such as mixtures of glycerol mono-, di-, and di-monoesters of macrogoles with molecular weights within the range of 200 to 4000 g / mol, for example macrogolglycerol caprilocaprate, macrogolglycerol laurate, cocoa macrogolglycerol, macrogolglycerol linoleate, macrogol-20-glycerol monostearate, macrogol-6- glycerol caprilocaprate, macrogolglycerol oleate; macrogolglycerol stearate, macrogolglycerol hydroxystearate (for example Cremophor® RH 40), and macrogolglycerol ricinoleate (for example Cremophor® EL);

polyoxyethylene fatty acid esters, the fatty acid having preferably between about 8 and about 18 carbon atoms, for example macrogol oleate, macrogol stearate, macrogol 15-hydroxystearate, 12-hydroxystearic acid polyoxyethylene esters, such as of the type known and commercially available under the trade name "Solutol HS 15"; preferably according to the general formula (ll-c)

CH3CH2- (OCH2CH3) n-O-CO- (CH2) mCH3 (ll-c)

where n is an integer from 6 to 500, preferably from 7 to 250, especially preferably from 8 to 100, even more preferably from 9 to 75, even more preferably from 10 to 50, even more preferably from 11 to 30, completely preferably from 12 to 25 and in particular from 13 to 20; and m is an integer from 6 to 28, especially preferably from 6 to 26, even more preferably from 8 to 24, even more preferably from 10 to 22, even more preferably from 12 to 20, of totally preferred form from 14 to 18 and in particular 16;

polyoxyethylene fatty alcohol ethers, for example macrogolcetilestearyl ether, macrogolaryl ether, macrogololethyl ether, macrogolesterethyl ether;

block copolymers of polyoxypropylene-polyoxyethylene (poloxamers);

sucrose fatty acid esters, for example sucrose dietearate, sucrose dioleate, sucrose dipalmitate, sucrose monostearate, sucrose monooleate, sucrose monopalmitate, sucrose monomiristate and sucrose monolaurate;

polyglycerol fatty acid esters, for example polyglycerol oleate;

polyoxyethylene esters of alpha-tocopheryl succinate, for example D-alpha-tocopheryl-PEG-1000-succinate (TPGS);

polyglycolized glycerides, such as those of the types known and commercially available under the trade names "Gelucire 44/14", "Gelucire 50/13" and "Labrasol";

reaction products of natural or hydrogenated castor oil and ethylene oxide, such as the various liquid surfactants known and commercially available under the trade name "Cremophor"; Y

partial fatty acid esters of multifunctional alcohols, such as glycerol fatty acid esters, for example mono- and trilauric, palmityl, stearyl and olefin esters, for example glycerol monostearate, glycerol monooleate, for example glyceryl monooleate 40, known and commercially available under the trade name "Peceol"; glycerol dibehenate, glycerol distearate, glycerol monolinoleate; ethylene glycol monostearate, ethylene glycol monopalmitoestearate, pentaerythritol monostearate.

Especially preferred surfactants of this class that are included in the pharmaceutical dosage form according to the invention are non-ionic surfactants with a hydrophilic-lipophilic balance (HLB) of at least 10, in particular non-ionic surfactants with a value HLB of at least 12, more particularly non-ionic surfactants having an HLB value between 14 and 16. Some examples of this type of surfactants are the "Tween® 80" and "Solutol® HS 15" surfactants mentioned above.

Solutol® HS-15 is a mixture of polyethylene glycol 660 12-hydroxystearate and polyethylene glycol. It is a white paste at room temperature that becomes liquid at approximately 30 ° C and an HLB of approximately 15.

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Tween® 80 [polyoxyethylene (20) sorbitan monooleate] is liquid at room temperature, has a viscosity of 375-480 mPas and an HLB of approximately 15.

In a preferred embodiment, the content of the surfactant is at least 0.001% by weight or at least 0.005% by weight, especially preferably at least 0.01% by weight or at least 0.05% by weight. weight, still more preferably at least 0.1% by weight, at least 0.2% by weight, or at least 0.3% by weight, even more preferably at least 0.4% by weight, at least 0.5% by weight, or at least 0.6% by weight, and in particular at least 0.7% by weight, at least 0.8% by weight, at least one 0.9% by weight, or at least 1.0% by weight, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment, in particular when the pharmaceutical dosage form contains an encapsulated core, the content of the surfactant is at least 10% by weight, especially preferably at least 15% by weight, even more preferably at least 20% by weight, even more preferably at least 25% by weight and in particular at least 30% by weight, based on the total weight of the composition that forms the nucleus. In a preferred embodiment, the content of the surfactant preferably ranges between 0.1% by weight and 95% by weight, especially preferably between 1% by weight and 95% by weight, even more preferably between 5% by weight and 90% by weight, even more preferably between 10% by weight and 80% by weight, most preferably between 20% by weight and 70% by weight, and in particular between 30% by weight and 75% by weight, based on the total weight of the composition that forms the nucleus.

In another preferred embodiment, in particular when the pharmaceutical dosage form consists of a tablet, the content of the surfactant preferably ranges from 0.001% by weight to 95% by weight, especially preferably between 0.01% by weight. and 50% by weight, still more preferably between 0.1% by weight and 20% by weight, even more preferably between 0.15% by weight and 15% by weight, totally preferably between 0.20% by weight and 10% by weight, and in particular between 0.25% by weight and 5% by weight, based on the total weight of the dosage form. In a preferred embodiment, the content of the surfactant is at most 25% by weight, particularly preferably at most 20% by weight, even more preferably at most 15% by weight, even more preferably at most 10% by weight, and in particular at most 5% by weight, based on the total weight of the pharmaceutical dosage form. If the dosage form is coated, the indication "% by weight" preferably refers to the weight of the surfactant by the total weight of the composition that forms the nucleus, that is, the pharmaceutical dosage form without its coating.

In a preferred embodiment, the content of the surfactant is within the range of 1.00 + 0.70% by weight, preferably 1.00 + 0.60% by weight, especially preferably 1.00 + 0, 50% by weight, even more preferably 1.00 + 0.40% by weight, even more preferably 1.00 + 0.30% by weight, most preferably 1.00 + 0, 20% by weight, and in particular 1.00 + 0.10% by weight.

The following table summarizes preferred embodiments A1 to A20 of the pharmaceutical dosage form according to the invention:

 Realization

 A'1 A2 A3 A *

 Inqredient

 Nat. Nat Content Nat. Content Nat. Content Nat. Content

 Pharmacologically active agent of general formula (1)

 Y1 0.04 + 0.035 Y1 0.04 + 0.025 Y2 0.04 + 0.02 Y3 0.04 + 0.01

 Surfactant

 Z1 2.75 + 2.50 Z2 1.00 + 0.50 Z3 1.00 + 0.20 Z4 1.00 + 0.10

 Realization

 A3 A ° A 'ab

 Inqredient

 Nat. Nat Content Nat. Content Nat. Content Nat. Content

 Pharmacologically active agent of general formula (1)

 Y1 0.32 + 0.30 Y1 0.32 + 0.25 Y2 0.32 + 0.20 Y3 0.32 + 0.10

 Surfactant

 Z1 2.75 + 2.50 Zl 1.00 + 0.50 Z3 1.00 + 0.20 Z4 1.00 + 0.10

 Realization

 Aa Alu A "A12

 Inqredient

 Nat. Nat Content Nat. Content Nat. Content Nat. Content

 Pharmacologically active agent of general formula (1)

 Y1 0.50 + 0.45 Y1 0.50 + 0.30 Y2 0.50 + 0.20 Y3 0.50 + 0.10

 Surfactant

 Z1 2.75 + 2.50 Z2 1.00 + 0.50 Z3 1.00 + 0.20 Z4 1.00 + 0.10

 Realization

 A13 A ™ A13 A10

 Inqredient

 Nat. Nat Content Nat. Content Nat. Content Nat. Content

 Pharmacologically active agent of general formula (1)

 Y1 0.60 + 0.55 Y1 0.60 + 0.40 Y2 0.60 + 0.20 Y3 0.60 + 0.10

 Surfactant

 Z1 2.75 + 2.50 Zl 1.00 + 0.50 Z3 1.00 + 0.20 Z4 1.00 + 0.10

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where

nat. refers to the chemical nature of the ingredient;

content refers to the content of the ingredient in% by weight with respect to the total weight of the core;

Y1 represents the pharmacologically active agent according to the general formula (I) or a salt

physiologically acceptable thereof;

Y2 represents the pharmacologically active agent according to the general formula (I ') or a salt

physiologically acceptable thereof;

Y3 represents (1r, 4r) -6'-fluor-N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -

4-amine, or (1r, 4r) -6'-fluor-N-methyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3,4 , b] indole] -4-amine, or a physiologically acceptable salt thereof;

Z1 represents a surfactant with an HLB value of at least 10;

Z2 represents a non-ionic surfactant with an HLB value of at least 30;

Z3 represents a surfactant anionic agent selected from the group consisting of sodium lauryl sulfate (sodium dodecyl sulfate, for example Texapon® K12), sodium cetyl sulfate (for example Lanette E®), sodium cetyl stearyl sulfate, sodium stearyl sulfate, dioctylsulfosuccinate sodium (sodium docusate), di- [2-ethylhexyl] -succinate; and the corresponding potassium or calcium salts thereof;

Z4 represents sodium lauryl sulfate.

For example, according to the table shown above, embodiment A9 refers to a pharmaceutical dosage form according to the invention containing the pharmacologically active agent according to the general formula (I) in an amount of 0.50 + 0, 45% by weight and a surfactant having an HLB value of at least 10 in an amount of 2.75 + 2.50% by weight, based on the total weight of the dosage form.

In a particularly preferred embodiment,

- the pharmaceutical dosage form contains a surfactant with an HLB value of at least 10 in an amount of at least 0.01% by weight, based on the total weight of the pharmaceutical dosage form; I

- the pharmaceutical dosage form contains between 0.01% and 95% of the pharmacologically active agent (A); I

- the pharmaceutical dosage form has a weight between 0.1 mg and 2,000 mg; I

- the pharmaceutical dosage form contains a polymer with a molecular weight between 1,000 g / mol and 15 million g / mol; I

- the pharmaceutical dosage form consists of a pill; I

- the pharmaceutical dosage form is prepared by means of wet granulation or direct tablet formation; I

- the pharmaceutical dosage form contains the pharmacologically active agent according to the general formula (I) in a dose between 10 pg and 50 pg or between 300 pg and 500 pg; I

- the pharmaceutical dosage form provides an immediate release of the pharmacologically active agent according to the general formula (I) in vitro according to Ph. Eur .; I

- tmax is within the range of 0.5 to 16 hours; I

- the AUC0-t / dose ratio is within the range of 0.5 to 16.5 h / m3; I

- the Cmax / dose ratio is in the range of 0.06 to 1.69 m-3.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is a tablet, chewable tablet, chewing gum, coated tablet or powder, optionally filled in a capsule, but particularly preferably a tablet.

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In another preferred embodiment, the pharmaceutical dosage form according to the invention is present in a multiparticulate form, preferably in the form of a micropatch, microcapsule, granulate or pfldora, optionally filled in a capsule or tablet forming a tablet.

In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention is a pill, preferably with a diameter of 6 + 3.0 mm, preferably 6 + 2.5 mm, especially preferably 6 + 2.0 mm , still more preferably 6 + 1.5 mm, totally preferred 6 + 1.0 mm, and in particular 6 + 0.5 mm.

The pharmaceutical dosage form according to the invention may contain pharmaceutical excipients, including non-sticks, binders, disintegrants, fillers, diluents, fluidizers, lubricants and conventional preservatives, known to those skilled in the art.

A suitable non-stick that may be contained in the pharmaceutical dosage form is magnesium stearate. In a preferred embodiment, the nonstick content is within the range between 0.001 and 5.0% by weight.

In a preferred embodiment, the pharmaceutical dosage form according to the invention also contains a binder. Suitable binders include, but are not limited to, gelatin, cellulose, modified cellulose such as microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol; Polyvinylpyrrolidone and / or microcrystalline cellulose are especially preferred. In a preferred embodiment, the binder content is within the range between 0.001 and 30% by weight, especially preferably between 0.1 and 25% by weight.

In a preferred embodiment, the pharmaceutical dosage form according to the invention also contains a filler and / or diluent material, preferably, but not exclusively, selected from the group consisting of cellulose, calcium diphosphate, lactose, sucrose, glucose, mannitol, sorbitol and calcium carbonate. Microcrystalline cellulose and lactose are especially preferred. In a preferred embodiment, the content of filler material and / or diluent is within the range between 0.001 and 90% by weight, especially preferably between 0.1 and 80% by weight, completely preferably between 10 and 75% by weight.

In a preferred embodiment, the pharmaceutical dosage form according to the invention also contains a lubricant such as magnesium stearate, stearic acid and stearin. In a preferred embodiment, the lubricant content is within the range between 0.001 and 5.0% by weight.

In a preferred embodiment, the pharmaceutical dosage form according to the invention also contains a disintegrant, such as cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone and sodium starch glycolate. In a preferred embodiment, the disintegrant content is within the range of 0.001 to 5.0% by weight.

The pharmaceutical dosage form may also contain at least one preservative. Suitable preservatives include, but are not limited to, antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; cystephine, methionine, cfric acid, sodium citrate, methylparaben and propylparaben.

In a preferred embodiment, the pharmaceutical dosage form further contains a coating, in particular a polymer based coating, more particularly a polyvinyl alcohol based coating, such as those commercially available under the trade name "Opadry".

Preferably, the coating protects the pharmaceutical dosage form against moisture, but dissolves rapidly in gastric juices. Preferably, the coated dosage form has a disintegration time of less than 5 minutes in gastric juices, especially preferably at most 4.5 minutes, even more preferably at most 4 minutes, even more preferably at most 3 , 5 minutes, even more preferably for a maximum of 3 minutes, totally preferably for a maximum of 2.5 minutes and in particular for a maximum of 2 minutes.

For the production of the pharmaceutical dosage forms according to the invention, the various solid auxiliary substances and the pharmacologically active agent according to the general formula (I) are preferably homogenized, processed by wet granulation, dry or melting to form granules, and compress to form pills. Alternatively they are produced by direct pellet formation from the auxiliary substances and the pharmacologically active agent according to the general formula (I).

In a preferred embodiment, the pharmaceutical dosage form is prepared by wet granulation from a granulation fluid containing the pharmacologically active agent according to the general formula (I), in particular from an aqueous granulation fluid that contains said agent

pharmacologically active and the surfactant. Preferably, the resulting granulation fluid is sprayed from above or sprayed from below on a solid formulation containing at least one auxiliary substance to produce compressible granules, which may optionally be mixed with other auxiliary substances before compressing them into tablets.

Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment of pain.

Another aspect of the invention relates to a method for the treatment of pain that consists of administering orally twice a day, once a day or less frequently the pharmaceutical dosage form according to the invention to a subject than the needs to.

Preferably, the pain is selected from acute, visceral, neuropathic or chronic pain.

EXAMPLES

Prophetic examples:

Below, in Table 1, prophetic examples of pharmaceutical dosage forms according to the invention are provided. Its compositions are given by way of example and it should be understood that the ingredients, the amount thereof and the method for obtaining the dosage form may vary.

For example, the ingredients of the following examples can be divided into intragranular and extragranular ingredients, as well as ingredients from which a granulated solution is formed in order to process the dosage forms by fluidized bed granulation according to the inventive example 1; or the dosage forms can be processed by an alternative process, such as dry granulation or direct compression.

Table 1

 Ingredients [mg]

 PE-1 PE-2 PE-3 PE-4 PE-5 PE-6

 Lactose monohydrate

 69.65 69.65 64.00 64.00 59.65 59.65

 Avicel® (PH 101 or PH 102)

 20.00 20.00 25.00 25.00 30.00 30.00

 Croscarmellose sodium

 3.00 3.00 2.50 2.50 3.00 3.00

 Compound (I'b)

 0.60 0.60 0.30 0.30 0.60 0.60

 Polyvinylpyrrolidone

 5.00 5.00 5.50 5.50 5.00 5.00

 Sodium Cetilestearyl Sulfate

 1.00 - 2.00 - 1.00 -

 Dioctyl Sulfosuccinate Sodium

 - 1.00 - 2.00 - 1.00

 Magnesium stearate

 0.75 0.75 0.70 0.70 0.75 0.75

25 Non-prophetic examples:

The following examples further illustrate the invention, but are not intended to limit the scope thereof.

Example 1:

30 Pharmaceutical dosage forms were produced by fluidized bed granulation according to the following compositions:

Table 2

 Ingredients

 Cont. (Dose 40 pg) Cont. (Dose 600 pg)

 % in weigh

 Amount per pill [mg]% by weight Amount per pill [mg]

 Intergranular

 Lactose Monohydrate (200 M)

 50.21 50.21 49.65 49.65

 Lactose Monohydrate (100 M)

 20.00 20.00 20.00 20.00

 Avicel® PH101

 10.00 10.00 10.00 10.00

 Croscarmellose sodium

 1.50 1.50 1.50 1.50

 Granulation Solution

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 Ingredients

 Cont. (Dose 40 pg) Cont. (Dose 600 pg)

 % in weigh

 Amount per pill [mg]% by weight Amount per pill [mg]

 Compound (I'b)

 0.04 0.04 0.6 0.6

 Polyvinylpyrrolidone

 5.00 5.00 5.00 5.00

 Sodium lauryl sulfate

 1.00 1.00 1.00 1.00

 Purified water

 - - - -

 Extragranular

 Croscarmellose sodium

 1.50 1.50 1.50 1.50

 Avicel® PH102

 10.00 10.00 10.00 10.00

 Magnesium stearate

 0.75 0.75 0.75 0.75

The ingredients Avicel® PH101 and Avicel® PH102 are microcrystalline celluloses with different average particle sizes (50 and 100 microns). The purified water was used as part of the granulation fluid, but was removed during the granulation process.

General procedure

For the fluidized bed granulation process, all intergranular ingredients [lactose monohydrate (200M and 100M), Avicel® PH101, croscarmellose sodium] were weighed and screened through a 710 micron sieve in a 5 l Pharmatech tank. Then, the material was mixed for 10 minutes at 25 rpm using a Pharmatech mixer. The granulation solution was prepared by dissolving sodium lauryl sulfate in 600 g of purified water. Then 400 g of the corresponding solution was used to dissolve the pharmacologically active agent according to formula (I ') (1,1- (3-methylamino-3-phenylpentamethylene) -6-fluor-1,3,4,9 -tetrahydropyran [3,4-b] indole (trans)) and the binder (polyvinylpyrrolidone) to form a drug suspension. The drug suspension was sprayed from above on the intragranular material at a suitable rate using Diosnaminilab machine to obtain compressible granules. The compressible granules were then added to the extragranular ingredients (croscarmellose sodium, Avicel® PH102, magnesium stearate) and mixed. Then the tablet compression was carried out on a Manesty F3 single die compression machine using a 6.00 mm NCCP tool. The tablets were coated by means of the OPADRY® AMB polyvinyl alcohol based coating system.

For the dosage of 50 pg, the determined content of the decomposition product 6'-fluor-4-phenyl-4 ', 9'- dihydro-3'H-spiro [cyclohex-3-eno-1,1'-pyran [ 3.4, b] indole] after storage at 25 ° C and a RH of 60%, and after storage at 40 ° C and a RH of 75%, it was <0.1% after 6 months.

Example2 (not corresponding to the invention):

Clinical studies were conducted to determine the analgesic efficacy and tolerability of single doses of the compound according to formula (I'b) (200 pg, 400 pg and 600 pg, based on the content of the free base; oral solution of compound hemicitrate (I'b) in Macrogol 400) compared to those of morphine (60 mg, controlled release form) and placebo in patients with acute postoperative pain after orthopedic surgery (bunionectomfa).

To this end, 258 patients of both sexes were included in groups in a double-blind, randomized, placebo-controlled clinical trial in parallel groups. The treatment groups were well balanced with respect to the demography and characteristics of the baseline, with a slight imbalance in the baseline of pain and ethnicity.

After surgery, all patients were initially treated with local postoperative anesthesia through a poplfteo block. Due to the different kinetics of the compound according to formula (I'b) and morphine, patients were treated with one of the two drugs or with placebo at slightly different times:

One hour before interrupting the poplfteo block, patients were randomized and part of them were given a single dose of the compound according to formula (I'b) (200 pg, 400 pg or 600 pg) or placebo, while the others received morphine or placebo 2 hours after the interruption of the poplfteo block.

The final parameter of the primary efficacy evaluation was the absolute intensity of pain over a 24-hour period. Pain intensity was measured using a numerical rating scale (NRS) of 11 points. At each moment, patients were instructed to evaluate the current intensity of their pain in relation to a numerical rating scale of 11 points. A score of zero represented absence of pain and a score of 10 represented the worst possible pain. The evaluations

of the programmed pain that were missing for the patients were attributed to the last observation made (LOCF - lastobservationcarried forward). Figure 1 shows the averages of the resulting NRS values over a 24 hour period.

The sum of the differences in pain intensity over different time periods was analyzed using a covariance analysis model (ANCOVA) with factors for the treatment and the place and score of the baseline of the intensity of the pain (using the NPRS pain intensity score). Only subjects were included for whom the intensity of baseline pain was not lacking. Table 3 shows a summary of the analyzes corresponding to the period of 2 to 10 hours. The resulting p values are summarized in Table 4.

10 Table 3

 n average MC EE average MC Aplacebo EE Value p

 Placebo

 45 49.13 2.85

 Compound (I'b) 200 pg

 52 46.05 2.78 -3.08 3.49 0.3776

 Compound (i'b) 400 pg

 47 35.28 2.81 -13.85 3.57 0.0001

 Compound (I'b) 600 pg

 55 35.15 2.67 -13.98 3.45 <0.0001

 Morphine, controlled release 60 mg

 49 42.01 2.83 -7.12 3.54 0.0454

MC mean: least squares means: EE: statistical error

Table 4

 P values (sum of pain intensity dif.)

 2-6 h 2-10 h 2-12 h 2-14 h 2-18 h 2-24 h

 Compound (I'b) 200 pg

 0.4514 0.3776 0.3387 0.3427 0.3205 0.2923

 Compound (I'b) 400 pg

 0.0009 0.0001 <0.0001 0.0001 0.0005 0.0008

 Compound (I'b) 600 pg

 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 0.0001

 Morphine, controlled release 60 mg

 0.4664 0.0454 0.0084 0.0036 0.0014 0.0005

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Therefore, a statistically significant difference was observed in the primary parameter between the groups that received a dose of 400 pg or 600 pg of the compound (I'b) and the placebo groups. In contrast, no significant difference was observed in the case of the groups that received a dose of 200 pg of the compound (I'b).

20 Tables 5 and 6 summarize the emerging adverse treatment events (ASD (s) - treatmentemergent adverse events) experienced by the five treatment groups.

Table 5

 Placebo Comp. (I'b) 200 pg Comp. (I'b) 400 pg Comp. (I'b) 600 pg Morphine 60 mg

 Subjects TEAE (s) (n (%)) Related (n (%)) Serious (n (%))

 32 (68.1) 17 (36.2) 1 (2.1) 37 (67.3) 24 (43.6) 0 38 (77.6) 32 (65.3) 0 48 (84.2) 43 (75.4) 0 46 (92.0) 42 (84.0) 0

 Total amount TEAE (n)

 74 75 125 198 144

 Related (n (%))

 32 (43.2) 37 (49.3) 74 (59.2) 146 (73.7) 99 (68.8)

 Subjects with AAG

 1 (2.1) 0 0 0 0

 Deaths

 0 0 0 0 0

TEAE: emerging adverse treatment event: AAG: serious adverse event

Table 6

 Placebo Comp. (I'b) 200 pg Comp. (I'b) 400 pg Comp. (I'b) 600 pg Morphine 60 mg

 Sickness

 17.0 29.1 49.0 64.9 66.0

 Vomit

 2.1 9.1 20.4 49.1 40.0

 Dizziness

 6.4 20.0 22.4 26.3 24.0

 Drowsiness

 2.1 1.8 10.2 14.0 16.0

 ASAT increase

 2.1 1.8 6.1 1.8 2.0

 Hot flushes

 0 1.8 4.1 7.0 4.0

 Pruritus

 0 0 6.1 3.5 2.0

 Hyperhidrosis

 0 0 0 5.3 6.0

100% = total number of subjects in the corresponding ASAT treatment group: aspartate aminotransferase

5 From Tables 5 and 6 it is clear that the four active treatments were well tolerated under these circumstances and that the most frequent adverse events are in line with what is expected of the opioid-p receptor agonists. In the group of patients treated with the compound (I'b), the incidence of adverse events increased with the dose, and in the case of the 600 pg dose the incidence of adverse events was comparable to that of the group of patients treated with morphine.

10 Example 3:

Clinical studies were conducted to determine the bioavailability of a tablet formulation containing the compound (I'b) in a dose of 400 pg compared to an oral solution of hemicitrate of the compound (I'b) (400 pg, 400 pg / ml oral solution) in a formulation of Macrogol 400 after a simple oral administration. Twenty-four healthy white male subjects were included in a randomized, open, cross-sectional clinical trial of three rounds in a single center. The main pharmacokinetic parameters were AUC0-t, AUC0-72h and Cmax.

The results are summarized in Tables 7 to 9.

Table 7

 Pharmacokinetic Parameter

 tmax [h] Cmax [pg / ml] AUC0-72h [hpg / ml] AUC0-t [hpg / ml]

 400 pg / ml oral solution

 6.00 (2.08; 6.00) 120 + 45.9 (38.3%) 2861 +1251 (43.7%) 4148 + 2773 (66.8%)

 400 pg pill

 6.00 (3.50; 10.0) 135 + 52.5 (38.8%) 3066 + 1225 (40.0%) 4501 + 2658 (59.1%)

N = 22; The table presents the arithmetic mean ± the standard deviation (coefficient of variation).

20 Table 8

 Comparison pills / oral solution

 Cmax AUC0-72h AUC0-t

 400 pg pill / 400 pg / ml oral solution

 108% (101% -118%) 108% (102% -115%) 110% (103% -118%)

Table 9

 Total number of subjects (N) Subjects with TEEA (s) TEAE (S)

 n% e

 400 pg pill

 23 * 14 60.9 21

 400 pg / ml oral solution

 24 19 79.2 40

n: number of subjects with at least one TEAE (adverse event emerging from treatment); %: corresponding proportion of subjects experiencing TEAE (s); e: TEAE number (s); *: 1 abandonment 25 due to an unrelated adverse event.

Thus, the relative bioavailability of the 400 pg and 400 pg / ml tablet of oral solution based on AUC0-72h was 108%, with 90% CI within the range of 80% to 125% used to evaluate bioequivalence.

The relative bioavailability of the 400 pg and 400 pg / ml tablet of oral solution based on Cmax was also 108%, with 90% CI within the range of 80% to 125% used to assess bioequivalence.

The administrations of simple oral doses of 400 pg of the compound (I'b) were safe and well tolerated independently of the galenic formulation. There were no serious adverse events.

Claims (9)

5 2. 10 3. Four. fifteen 5. twenty 6. 25 7. 30 8. Pharmaceutical dosage form for oral administration twice a day, once a day or less frequently, containing a pharmacologically active agent according to the general formula (I) image 1 where R is -H or -CH3, or a physiologically acceptable salt thereof, and a surfactant, the surfactant having an HLB value of at least 10. Pharmaceutical dosage form according to claim 1, characterized in that it is a pill. Pharmaceutical dosage form according to claim 1 or 2, characterized in that it additionally contains one or more pharmaceutical excipients selected from the group consisting of non-sticks, binders, disintegrants, fillers, diluents, fluidizers, lubricants and preservatives. Pharmaceutical dosage form according to any of the preceding claims, characterized in that the content of surfactant is at least 0.001% by weight, with respect to the total weight of the pharmaceutical dosage form. Pharmaceutical dosage form according to any of the preceding claims, characterized in that it is prepared by wet granulation from an aqueous granulation fluid containing the pharmacologically active agent according to the general formula (I) and the surfactant. Pharmaceutical dosage form according to any of the preceding claims, characterized in that the surfactant is selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid partial esters and sulfuric acid esters. Pharmaceutical dosage form according to any of the preceding claims, characterized in that the pharmacologically active agent according to the general formula (I) image2 where R has the meaning defined in claim 1. Pharmaceutical dosage form according to any of the preceding claims, characterized in that the pharmacologically active agent according to the general formula (I) is (1r, 4r) -6'-fluor-N, N-dimethyl-4-phenyl-4 ' , 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3,4, b] indole] -4- 10 fifteen amine, (1r, 4r) -6'-fluor-N-methyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyran [3,4, b] -indole] -4- amine, or a physiologically acceptable salt thereof. 9. Pharmaceutical dosage form according to any of the preceding claims, characterized in that it releases after 30 minutes under conditions in vitro in 900 ml of artificial gastric juices, pH 1.2, at least 80% by weight of the pharmacologically active agent according to the general formula (I), based on the total amount of the pharmacologically active agent according to the general formula (I) originally contained in the dosage form. 10. Pharmaceutical dosage form according to any of the preceding claims, characterized in that it contains the pharmacologically active agent according to the general formula (I) in a dose of 10 pg at 50 pg or 300 pg at 500 pg. 11. Pharmaceutical dosage form according to any of the preceding claims for use in the treatment of pain. 12. Pharmaceutical dosage form according to claim 11, characterized in that the pain is selected from acute visceral, neuropathic or chronic pain.